The efficacy of alpha‐lipoic acid in the management of burning mouth syndrome: An updated systematic review of randomized controlled clinical trials

Abstract Background and Aims Burning mouth syndrome (BMS) causes burning or uncomfortable feelings in the oral cavity without any obvious injuries. This condition's etiopathogenesis is still unknown, consequently, BMS management is very challenging. Alpha‐lipoic acid (ALA) is a naturally occurring potent bioactive compound that has been found to be useful in the management of BMS in many studies. Therefore, we conducted a comprehensive systematic review to investigate the usefulness of ALA in the management of BMS based on randomized controlled trials (RCTs). Methods Different electronic databases, including PubMed, Scopus, Embase, Web of Science, and Google Scholar, were extensively searched to find relevant studies. Results This study included nine RCTs that matched the inclusion criteria. In most studies, ALA was given at a dose of 600–800 mg/day, with up to two months of follow‐up. The majority of studies (six out of nine studies) indicated that ALA was more effective in BMS patients than in the placebo‐controlled group. Conclusions This comprehensive systematic review provides evidence of the positive outcomes of the treatment of BMS with ALA. However, more research might be needed before ALA can be considered the first‐line therapy for BMS.

and nutritional deficiencies, and/or psychological problems like anxiety and depression. 10 The exact pathophysiology of BMS is still not well understood, and there is much debate around this topic in the scientific literature.
Scientific evidence suggests that the neuropathic abnormalities in the tiny nerve fibers of the oral mucosa and/or in certain brain regions are associated with a burning sensation in the oral mucosa manifesting as pain, dysgeusia, and xerostomia. 11 Owing to the limited knowledge of its pathogenesis with a large variety of associated factors, the treatment for BMS is challenging for physicians. According to the literature, different types of drugs, medications, and other interventions have been proposed for the symptomatic treatment of BMS, but there is presently no widely approved regimen available for the management of BMS. 12 Alphalipoic acid (ALA) is a naturally obtained bioactive compound that has potent antioxidant, anti-inflammatory, and neuroprotective effects.
ALA has the ability to scavenge reactive oxygen species in most parts of the body, both inside and outside of cells, and it is referred to as the universal antioxidant. It is made by the body in very small amounts, and it can also be found in foods like spinach, broccoli, and meats. ALA has been found to be effective in the management of BMS in many studies. Although ALA has reportedly been researched in the treatment of BMS, the outcomes are ambiguous. 13,14 Therefore, the purpose of this study was to compile a comprehensive summary of the findings of randomized controlled clinical trials that assessed the effectiveness of ALA on BMS.

| Literature search strategy
The Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) statement was employed as a standard guideline to conduct this study 15 (Supporting Information: file 1). To find relevant published studies up to November 2022, we performed an electronic database search in PubMed/Medline, Scopus, Embase, Web of Science, and Google Scholar. The following keywords, such as "lipoic acid, "alpha-lipoic acid," "α-lipoic acid," "ALA," "burning mouth syndrome," "supplementation," "treatment," "management," "prevention," "clinical trial," "randomized clinical trial," "RCT," and "randomized controlled clinical trial" were used in electronic databases searching. Additionally, the reference lists of all included articles were checked to avoid missing any related studies.

| Inclusion and exclusion criteria
The PICOS (population, intervention, comparison, outcomes, and study design) model was utilized to set up the selection criteria (inclusion and exclusion criteria) of this systematic review. The highlighted inclusion criteria of this study were as follows: (i) studies were published in a peer-reviewed English journal; (ii) the study population was over the age of 18; (iii) the study type was randomized controlled clinical trials; (iv) studies were available in full text (editorial, conference abstracts, and case reports were excluded).
Relevant studies published in other languages than English, studies without any control or placebo group, and any observational studies were excluded from this systematic review.

| Quality assessment
We assessed the quality of each study based on the Cochrane Collaboration Tool. 16 This tool consists of the following six items to assess, including studies: (i) the randomization process; (ii) allocation concealment; (iii) participant, personnel, and outcomes; (iv) missing outcome data; (v) selective outcome reporting; and (vi) other possible sources of bias. Overall, the final quality assessments of each score were ranked as good, fair, and unclear.

| Search result
Our search approach identified a total of 315 relevant publications.
Among them, after removing duplicate records (n = 255), and screening by title and abstract (n = 37), we selected 23 articles for final evaluation. Nine studies out of 23 publications were finally considered in the present systematic review. Figure 1 depicts the steps used to conduct a literature search, evaluate potential articles, and determine which ones are appropriate for inclusion in the research.

| Study characteristics
The demographic study characteristics of the included randomized clinical trials are summarized in Table 1. Four studies were conducted in Italy, 13,[17][18][19] two in Spain, 20,23 two in Brazil, 21

| Results of studies
Nine studies reported the efficacy of ALA in the management of BMS (Table 1). In all studies, oral supplementation of ALA was given at a dose of 600-800 mg/day, divided into two or three times daily for two months in most studies. Among nine studies, only two studies did not show any significant improvement in the ALA treatment group 13,20 and one study reported a level of reduction in burning symptoms for both treatments with no significant differences between the treatment and control group. 21 The other six studies reported superior improvement in the ALA treatment group in comparison to the placebocontrolled group. 17

| Quality assessment
According to the Cochrane guidelines, most studies were rated with a good quality score, which means reported studies have a low risk of bias (Table 2). All studies followed the randomization process, and outcomes were carefully checked and enlisted in an MS excel sheet.

| DISCUSSION
BMS is a poorly understood chronic condition of the intraoral mucosa owing to its etiology and treatment. It is characterized by discomfort or pain in the absence of a visible lesion to the mouth, but numerous local, systemic, and psychological variables have been identified as potential causes of BMS. 8,9 Although there is currently no effective protocol for the management of BMS, several studies have found the therapeutic efficacy of ALA in BMS patients, which can be considered a potential treatment option for BMS. ALA is a naturally obtained bioactive compound that acts as a nutritional cofactor for mitochondrial enzymes and is found to be effective in the treatment of several diseases, including diabetic neuropathy, Alzheimer's disease, and peripheral artery disease, due to its potent free-radical scavenger activity. 25  writing-review and editing.

ACKNOWLEDGEMENT
This study didn't receive any specific grants from any organizations like the public, commercial, or non-profit organizations.

CONFLICT OF INTEREST STATEMENT
Sujan Banik is an Editorial Board member of Health Science Reports and a corresponding author of this article. He was excluded from all editorial decision-making related to the acceptance of this article for publication in this journal. The other authors have declared that they have no competing interests.

DATA AVAILABILITY STATEMENT
All data relevant to the study are included in the article.

TRANSPARENCY STATEMENT
The lead author Sujan Banik affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.